Characterizing novel adult neuronal survival factors

描述(申请人提供)：神经元的功能和生存能力通常依赖于分泌的生长因子。虽然神经营养因子在发育中的神经系统中被广泛研究，但神经营养因子在成人大脑中是重要的，并已作为成人神经退行性疾病的治疗手段进行了研究。因此，在成人大脑中分离具有神经营养活性的蛋白质，对于我们理解成熟神经系统中神经元的完整性和功能的维持，以及作为一系列神经和精神疾病的潜在治疗剂，都具有广泛的意义。 我们鉴定了一个脑特异性蛋白家族(Cbln1-Cbln4)，称为突触营养因子，具有成人神经营养因子的特性。Cbln1和Cbln3是分泌的糖蛋白，在成熟的小脑颗粒细胞中共表达，形成与肿瘤坏死因子-α(TNFpha)结构相关的三聚体复合体。在小鼠中，通过同源重组消除Cbln1会导致共济失调、颗粒细胞-浦肯野细胞突触相互作用的显著结构和生理缺陷，以及成年小脑颗粒神经元的进行性退化。因此，Cbln1是一类新的调节突触稳定性和功能以及神经元存活的因子的原型。值得注意的是，浦肯野细胞中孤儿谷氨酸Delta2受体(GluRdelta2)的丢失模仿了cbln1基因缺失小鼠的表型。因此，突触前Cbln1和突触后GluRdelta2可能是一条新的营养信号通路的组成部分。这种机制可能存在于大脑的其他地方，与人类的神经精神疾病(突触传递中断)和神经退行性疾病(神经元丢失和功能障碍)有关。 在这一应用中，我们利用TNFpha和GluRdelta2的结构和功能特性来阐明cbln1基因缺失小鼠神经缺陷的分子基础，并表征cbln1信号通路的组成部分。

DESCRIPTION (provided by applicant): The function and viability of neurons is frequently dependent upon secreted growth factors. Although most extensively investigated in the developing nervous system neurotrophic factors are important in the adult brain and have been examined as therapeutic modalities in adult neurodegenerative conditions. Therefore, the isolation of proteins in adult brain with neurotrophic activity could have broad implications both for our understanding of the maintenance of neuronal integrity and function in the mature nervous system and as potential therapeutic agents for a range of neurological and psychiatric disorders. We identified a family of brain-specific proteins (Cbln1-Cbln4), termed synaptotrophins that have properties of adult neurotrophic factors. Cbln1 and Cbln3 are secreted glycoproteins that are co-expressed in mature cerebellar granule cells and form trimeric complexes that are structurally related to tumor necrosis factor-alpha (TNFalpha). Elimination of Cbln1 through homologous recombination in mice causes ataxia, marked structural and physiological defects in granule celI-Purkinje cell synaptic interactions and the progressive degeneration of adult cerebellar granule neurons. Thus Cbln1 is the prototype of a novel class of factor that regulates synaptic stability and function and neuronal survival. Remarkably, loss of the orphan glutamate delta2 receptor (GluRdelta2) in Purkinje cells mimics the phenotype of the cbln1-null mouse. Thus, presynaptic Cbln1 and postsynaptic GluRdelta2 may be components of a novel trophic signaling pathway. This mechanism likely exists elsewhere in brain having implications for neuropsychiatric (disrupted synaptic transmission) and neurodegenerative disorders (neuronal loss and functional impairment) in man. In this application we take advantage of the structural and functional properties of TNFalpha and GluRdelta2 to elucidate the molecular bases of the neural deficits in cbln1-null mice and characterize the components of the Cbln1 signaling pathway.